Presentation Description :
Optic neuropathies result when there is impaired axoplasmic flow from the retinal ganglion cell body, across the laminar cribrosa and towards the lateral geniculate nucleus. Dynamic processing of aqueous humor (AqH), cerebral spinal fluid (CSF) and blood delivery all influence axoplasmic flow and impact optic nerve anatomy and physiology. These dynamic processes are fairly well understood in phenomenological terms but recent genome-wide association studies (GWAS) provide more insights into how these processes could impact optic nerve health. For example, GWAS of intraocular pressure (IOP), which provides a readout for AqH dynamics, reveals 7 loci: TMCO1, FDNC3B, CAV1/CAV2, ABCA1, NUP160, PTPRJ and GAS7. Collectively these loci are associated with an increased risk of primary open-angle glaucoma (POAG). Integrated Molecular Pathway Level Analysis accounting for these markers indicate that nitric oxide signaling and lipid metabolism could impact IOP level and ultimately optic nerve health. A GWAS of normal tension glaucoma points to DNaseI hypersensitivity sites in choroidal plexus epithelial cells and ocular ciliary epithelial cells, implying that impaired CSF dynamics could make the optic nerve vulnerable to relatively normal IOP. Finally, ocular perfusion pressure (systemic blood pressure minus IOP), a surrogate measure for blood delivery to the optic nerve, is associated with the prevalence and progression of open angle glaucoma (OAG). We formed a genetic risk panel from 27 diastolic blood pressure (DBP) genetic loci and found it was not associated with POAG in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD). Thus, while POAG shares genetic determinants with IOP, currently known DBP genetic loci contribute little to POAG risk. This suggests that pharmacological manipulation of blood pressure might drive the association between ocular perfusion pressure and OAG. Overall, there appears to be little overlap between the various known genetic biomarkers for the dynamic processes governing optic nerve health, although an intriguing interaction between caveolin and the ABC A1 transporter which plays a critical role in cholesterol efflux, could emerge as a future target to ameliorate vision loss from optic neuropathy while also contributing to overall systemic health.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.